Piperidine derivatives as modulators of chemokine receptors

ABSTRACT

The invention provides a compound of formula (I): wherein R 1 , R 2 , R 3 , R 3a , R 4 , R 4a , R 5 , and R 6  are as defined; or a pharmaceutically acceptable salt thereof or a solvate thereof; compositions containing these compounds, processes for preparing them and their use as modulators of chemokine activity (especially CCR5 activity)

The present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.

Pharmaceutically active piperidine derivatives are disclosed in EP-A1-1013276, WO00/08013, WO99/38514 and WO99/04794.

Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rôle in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small, secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C—X—C, or α) and Cys-Cys (C—C, or β) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.

The C—X—C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents that modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several chemokines, principally “regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MIP-1a and MIP-1b and monocyte chemoattractant protein-2 (MCP-2).

This results in the recruitment of cells of the immune system to sites of disease. In many diseases it is the cells expressing CCR5 that contribute, directly or indirectly, to tissue damage. Consequently, inhibiting the recruitment of these cells is beneficial in a wide range of diseases.

CCR5 is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor intemalisation with a CCR5 agonist protects cells from viral infection.

The present invention provides a compound of formula (I):

wherein:

-   -   R¹ is C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, heterocyclyl (itself         optionally substituted by C₁₋₄ alkyl), C₁₋₈ alkyl (optionally         substituted by C₃₋₆ cycloalkyl, C₅₋₆ cycloalkenyl, phenyl,         heteroaryl, S(O)_(p)R⁷, CO₂R⁸), C₃₋₆ alkenyl (optionally         substituted by phenyl, heteroaryl, S(O)_(q)R⁹, CO₂R¹⁰) or C₃₋₈         alkynyl;     -   R² is phenyl, heteroaryl, phenyl(C₁₋₄ alkyl) or heteroaryl(C₁₋₄         alkyl);     -   R³, R^(3a), R⁴ and R^(4a) are, independently, hydrogen or C₁₋₄         alkyl;     -   R⁵ is hydrogen, C₁₋₄ alkyl (optionally substituted by halogen,         hydroxy, C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, SH, C₁₋₄ alkylthio, cyano         or S(O)_(q)(C₁₋₄ alkyl)), C₃₋₄ alkenyl, C₃₋₄ alkynyl or C₃₋₇         cycloalkyl;     -   R⁶ is phenyl, heteroaryl, phenylNH, heteroarylNH,         phenyl(C₁₋₂)alkyl, heteroaryl(C₁₋₂)alkyl, phenyl(C₁₋₂ alkyl)NH         or heteroaryl(C₁₋₂ alkyl)NH;     -   R⁷ and R⁹ are, independently, C₁₋₄ alkyl, or, when p or q is 0,         C₁₋₄ acyl;     -   R⁸ and R¹⁰ are, independently, hydrogen or C₁₋₄ alkyl;     -   wherein the phenyl and heteroaryl rings of any of the foregoing         are independently optionally substituted by halo, cyano, nitro,         hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, S(O)_(m)C₁₋₄ alkyl,         S(O)₂NR¹¹R¹², NHS(O)₂(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄         alkyl)₂, NHC(O)NH₂, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), NHC(O)(C₁₋₄         alkyl), CO₂H, CO₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃, CHF₂,         CH₂F, CH₂CF₃ or OCF₃;     -   R¹¹ and R¹² are, independently, hydrogen or C₁₋₄ alkyl, or         together with a nitrogen or oxygen atom, may join to form a 5-         or 6-membered ring which is optionally substituted with C₁₋₄         alkyl, C(O)H or C(O)(C₁₋₄ alkyl);     -   m, p and q are, independently, 0, 1 or 2;     -   or a pharmaceutically acceptable salt thereof or a solvate         thereof.

Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.

The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.

Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl or iso-propyl.

Alkenyl and alkynyl groups and moieties are, for example, vinyl, allyl or propargyl.

Cycloalkyl is a mono-, bi- or tri-cyclic structure such as, for example, cyclopropyl, cyclopentyl, cyclohexyl or adamantyl.

Cycloalkenyl comprises 1 double bond and is, for example, cyclopentenyl or cyclohexenyl.

Acyl is, for example, carbonyl substituted by C₁₋₆ alkyl or optionally substituted phenyl.

Heterocyclyl is a non-aromatic 3, 4, 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example, aziridinyl, azetidinyl, oxetanyl, piperidinyl, 4,5-dihydro-oxazolyl, 4,5-dihydroimidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl or tetrahydrothiopyranyl (wherein the sulphur is optionally substituted with 1 or 2 oxygen atoms).

Heteroaryl is an aromatic 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heteroaryl is, for example, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, benzimidazolyl, benzo[b]furyl, benzo[b]thienyl, phthalazinyl, indanyl, benzthiazolyl or cinnolinyl.

Phenylalkyl is, for example, benzyl, 1-(phenyl)ethyl or 2-(phenyl)ethyl.

Heteroarylalkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 2-(pyridinyl)ethyl.

The group S(O)₂NR¹¹R¹² is, for example, S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl, S(O)₂N(C₁₋₄ alkyl)₂, S(O)₂(4-C(O)H-piperazin-1-yl) or S(O)₂(4-C(O)CH₃-piperazin-1-yl).

Phenyl(C₁₋₂ alkyl)NH is, for example, benzylamino. Heteroaryl(C₁₋₂ alkyl)NH is, for example, pyridinylCH₂NH, pyrimidinylCH₂NH or pyridinylCH(CH₃)NH.

In one particular aspect R¹ is C₃₋₇ cycloalkyl. In another aspect R¹ is cyclopropyl or cyclobutyl.

In a further aspect R² is optionally substituted phenyl (especially optionally substituted by halo, cyano, methyl, ethyl, methoxy, ethoxy, NH₂, NHCH₃, N(CH₃)₂, CF₃, CHF₂, CH₂F, CH₂CF₃ or OCF₃). In another aspect R² is optionally substituted phenyl (especially optionally substituted by halogen or CF₃). Halogen is especially chlorine or fluorine. It is especially preferred that phenyl is ortho- or meta-substituted. For example R² is unsubstituted phenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl or 4-CF₃-phenyl.

In a still further aspect R³ and R^(3a) are both hydrogen.

In yet another aspect R⁴ and R^(4a) are hydrogen or methyl.

In another aspect R⁴ is hydrogen or methyl and R^(4a) is hydrogen.

In a further aspect R⁴ and R^(4a) are hydrogen or methyl, and R³ and R^(3a) are all hydrogen.

In a still further aspect R³, R^(3a), R⁴ and R^(4a) are all hydrogen.

In another aspect R⁵ is hydrogen or C₁₋₄ alkyl (such as methyl, ethyl or iso-propyl), C₃₋₄ alkenyl (for example allyl), C₃₋₄ alkynyl (for example propargyl), C₃₋₇ cycloalkyl (for example cyclopropyl) or C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (for example cyclopropylCH₂).

In yet another aspect of the invention R⁵ is methyl, ethyl, allyl or cyclopropyl.

In a still further aspect R⁶ is preferably optionally substituted benzyl, especially benzyl singly substituted (such as in the 4-position) by S(O)₂(C₁₋₄)alkyl (such as S(O)₂CH₃) or S(O)₂NR⁹R¹⁰ {R⁹ and R¹⁰ are, independently, hydrogen or C₁₋₄ alkyl, or together with a nitrogen or oxygen atom, may join to form a 5- or 6-membered ring which is optionally substituted with C₁₋₄ alkyl, C(O)H or C(O)(C₁₋₄ alkyl)} (such as S(O)₂NH₂, S(O)₂NH(CH₃), S(O)₂N(CH₃)₂, S(O)₂(4-C(O)H-piperazin-1-yl) or S(O)₂(4-C(O)CH₃-piperazin-1-yl). The variables R⁹ and R¹⁰ are especially hydrogen.

In yet another aspect R⁶ is optionally substituted benzyl, especially benzyl singly substituted (such as in the 4-position) by halo (such as fluoro), S(O)₂(C₁₋₄)alkyl (such as S(O)₂CH₃) or S(O)₂NH₂.

In a further aspect R⁶ is optionally substituted benzyl, especially benzyl singly substituted (such as in the 4-position) by halo (such as fluoro) or S(O)₂(C₁₋₄)alkyl (such as S(O)₂CH₃).

In one aspect the present invention provides a compound of formula (Ia):

wherein R¹, R⁵ and R⁶ are as hereinbefore defined.

The following compounds illustrate the invention.

TABLE I All compounds in Table I are of formula (Ia) below. (Ia)

Com- pound LCMS No. R¹ R⁵ R⁶ (MH+) 1 Cyclobutyl Me CH₂Ph-4-F 452 2 Cyclobutyl Et CH₂Ph-4-F 466 3 Cyclopropyl Me CH₂Ph-4-F 438 4 CH₂-2-Thiophene Et CH₂Ph-4-S(O)₂Me 568 5 C(═CH₂)CH₂CO₂Me Et CH₂Ph-4-S(O)₂Me 570 6 CH(Me)CH₂SAc—(R) Et CH₂Ph-4-S(O)₂Me 588 7 CH₂S(O)₂Me Et CH₂Ph-4-S(O)₂Me 562 (M − H)+ 8 Cyclopropyl Et CH₂Ph-4-F 9 Cyclobutyl Et CH₂Ph-4-S(O)₂Me 10 Cyclopropyl Et CH₂Ph-4-S(O)₂Me 11 Cyclobutyl Et CH₂Ph-4-S(O)₂NH₂ 12 Cyclopropyl Et CH₂Ph-4-S(O)₂NH₂ 13 Cyclobutyl allyl CH₂Ph-4-S(O)₂Me 14 Cyclopropyl allyl CH₂Ph-4-S(O)₂Me 15 Cyclobutyl allyl CH₂Ph-4-S(O)₂NH₂ 16 Cyclopropyl allyl CH₂Ph-4-S(O)₂NH₂ 17 Cyclobutyl Cyclo- CH₂Ph-4-S(O)₂Me propyl 18 Cyclopropyl Cyclo- CH₂Ph-4-S(O)₂Me propyl 19 Cyclobutyl Cyclo- CH₂Ph-4-S(O)₂NH₂ propyl 20 Cyclopropyl Cyclo- CH₂Ph-4-S(O)₂NH₂ propyl

The compounds of formula (I) and (Ia) can be prepared as shown in Schemes 1 and 2 below.

A compound of formula (I) or (Ia) can be prepared by reacting a compound of formula (II):

with either an acid halide of formula R¹C(O)Cl in a suitable solvent (such as a chlorinated solvent, for example CH₂Cl₂), or an acid of formula R¹CO₂H in the presence of a suitable coupling agent and in a suitable solvent. Suitable coupling agents include PyBrOP™ (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate), EDCI (ethyl dimethylaminopropyl carbodiimide hydrochloride), HOBT (1-hydroxybenzotriazole), and DMAP (N,N-dimethylaminopyridine).

In a further aspect the invention provides processes for preparing the compounds of formula (I) or (Ia). Many of the intermediates in the processes shown in Schemes 1 and 2 are novel and these are provided as further features of the invention.

The compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)). Examples of these conditions are:

-   -   (1) (the respiratory tract) obstructive diseases of airways         including: chronic obstructive pulmonary disease (COPD) (such as         irreversible COPD); pulmonary fibrosis; asthma {such as         bronchial, allergic, intrinsic, extrinsic or dust asthma,         particularly chronic or inveterate asthma (for example late         asthma or airways hyper-responsiveness)}; bronchitis {such as         eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or         chronic rhinitis including rhinitis caseosa, hypertrophic         rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis         medicamentosa; membranous rhinitis including croupous, fibrinous         or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal         rhinitis including rhinitis nervosa (hay fever) or vasomotor         rhinitis; sarcoidosis; farmer's lung and related diseases; nasal         polyposis; fibroid lung or idiopathic interstitial pneumonia;     -   (2) (bone and joints) arthrides including rheumatic, infectious,         autoimmune, seronegative spondyloarthropathies (such as         ankylosing spondylitis, psoriatic arthritis or Reiter's         disease), Behcet's disease, Sjogren's syndrome or systemic         sclerosis;     -   (3) (skin and eyes) psoriasis, atopic dermatitis, contact         dermatitis or other eczmatous dermitides, seborrhoetic         dermatitis, lichen planus, phemphigus, bullous phemphigus,         epidermolysis bullosa, urticaria, angiodermas, vasculitides         erythemas, cutaneous eosinophilias, uveitis, alopecia areata or         vernal conjunctivitis;     -   (4) (gastrointestinal tract) Coeliac disease, proctitis,         eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,         ulcerative colitis, irritable bowel disease or food-related         allergies which have effects remote from the gut (for example         migraine, rhinitis or eczema);     -   (5) (Allograft rejection) acute and chronic following, for         example, transplantation of kidney, heart, liver, lung, bone         marrow, skin or cornea; or chronic graft versus host disease;         and/or     -   (6) (other tissues or diseases) Alzheimer's disease, multiple         sclerosis, atherosclerosis, inhibiting the entry of viruses into         target cells, Acquired Immunodeficiency Syndrome (AIDS), lupus         disorders (such as lupus erythematosus or systemic lupus),         erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type         I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE         syndrome, leprosy (such as lepromatous leprosy), peridontal         disease, sezary syndrome, idiopathic thrombocytopenia pupura,         disorders of the menstrual cycle, glomerulonephritis or cerebral         malaria.

The compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (ADS).

According to a further feature of the invention there is provided a compound of the formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR5 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof.

The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state, such as rheumatoid arthritis) in a warm blooded animal (such as man) suffering from, or at risk of, said disease, which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or solvate thereof.

The present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof or a solvate thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or arthritis (especially rheumatoid arthritis). [Respiratory disease is, for example, COPD, asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)} or rhinitis {acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}; and is particularly asthma or rhinitis].

The invention also provides a compound of the formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or arthritis (especially rheumatoid arthritis).

The invention also provides a compound of the formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in therapy (including prophylaxis); for example in the treatment of a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, such as in the treatment of rheumatoid arthritis.

The invention also provides a compound of the formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis.

In another aspect the present invention provides the use of a compound of the formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example in modulating chemokine receptor activity (especially CCR5 receptor activity (especially in the treatment of rheumatoid arthritis)) in a warm blooded animal, such as man).

The invention further provides the use of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:

-   -   (1) (the respiratory tract) obstructive diseases of airways         including: chronic obstructive pulmonary disease (COPD) (such as         irreversible COPD); asthma {such as bronchial, allergic,         intrinsic, extrinsic or dust asthma, particularly chronic or         inveterate asthma (for example late asthma or airways         hyper-responsiveness)}; bronchitis {such as eosinophilic         bronchitis}; acute, allergic, atrophic rhinitis or chronic         rhinitis including rhinitis caseosa, hypertrophic rhinitis,         rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa;         membranous rhinitis including croupous, fibrinous or         pseudomembranous rhinitis or scrofoulous rhinitis; seasonal         rhinitis including rhinitis nervosa (hay fever) or vasomotor         rhinitis; sarcoidosis; farmer's lung and related diseases; nasal         polyposis; fibroid lung or idiopathic interstitial pneumonia;     -   (2) (bone and joints) arthrides including rheumatic, infectious,         autoimmune, seronegative spondyloarthropathies (such as         ankylosing spondylitis, psoriatic arthritis or Reiter's         disease), Behcet's disease, Sjogren's syndrome or systemic         sclerosis;     -   (3) (skin and eyes) psoriasis, atopic dermatitis, contact         dermatitis or other eczmatous dermitides, seborrhoetic         dermatitis, lichen planus, phemphigus, bullous phemphigus,         epidermolysis bullosa, urticaria, angiodermas, vasculitides         erythemas, cutaneous eosinophilias, uveitis, alopecia areata or         vernal conjunctivitis;     -   (4) (gastrointestinal tract) Coeliac disease, proctitis,         eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,         ulcerative colitis, irritable bowel disease or food-related         allergies which have effects remote from the gut (for example         migraine, rhinitis or eczema);     -   (5) (Allograft rejection) acute and chronic following, for         example, transplantation of kidney, heart, liver, lung, bone         marrow, skin or cornea; or chronic graft versus host disease;         and/or     -   (6) (other tissues or diseases) Alzheimer's disease, multiple         sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome         (AIDS), lupus disorders (such as lupus erythematosus or systemic         lupus), erythematosus, Hashimoto's thyroiditis, myasthenia         gravis, type I diabetes, nephrotic syndrome, eosinophilia         fascitis, hyper IgE syndrome, leprosy (such as lepromatous         leprosy), peridontal disease, sezary syndrome, idiopathic         thrombocytopenia pupura or disorders of the menstrual cycle;         in a warm blooded animal, such as man.

In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of the compound, preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof or a solvent thereof (hereafter Compound X), for therapeutic or prophylactic use in humans:

(a)

Tablet I mg/tablet Compound X 100 Lactose Ph. Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (b)

Tablet II mg/tablet Compound X 50 Lactose Ph. Eur. 229 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (c)

Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur. 92 Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0 (d)

Capsule mg/capsule Compound X 10 Lactose Ph. Eur. 389 Croscarmellose sodium 100 Magnesium stearate 1.0 (e)

Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations     were carried out at room or ambient temperature, that is, at a     temperature in the range of 18-25° C.; -   (ii) organic solutions were dried over anhydrous magnesium sulphate;     evaporation of solvent was carried out using a rotary evaporator     under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath     temperature of up to 60° C.; -   (iii) chromatography unless otherwise stated means flash     chromatography on silica gel; thin layer chromatography (TLC) was     carried out on silica gel plates; where a “Bond Elut” column is     referred to, this means a column containing 10 g or 20 g of silica     of 40 micron particle size, the silica being contained in a 60 ml     disposable syringe and supported by a porous disc, obtained from     Varian, Harbor City, Calif., USA under the name “Mega Bond Elut SI”.     Where an “Isolute™ SCX column” is referred to, this means a column     containing benzenesulphonic acid (non-endcapped) obtained from     International Sorbent Technology Ltd., 1st House, Duffryn Industial     Estate, Ystrad Mynach, Hengoed, Mid Clamorgan, UK. Where “Argonaut™     PS-tris-amine scavenger resin” is referred to, this means a     tris-(2-aminoethyl)amine polystyrene resin obtained from Argonaut     Technologies Inc., 887 Industrial Road, Suite G, San Carlos, Calif.,     USA. -   (iv) in general, the course of reactions was followed by TLC and     reaction times are given for illustration only; -   (v) yields, when given, are for illustration only and are not     necessarily those which can be obtained by diligent process     development; preparations were repeated if more material was     required; -   (vi) when given, ¹H NMR data is quoted and is in the form of delta     values for major diagnostic protons, given in parts per million     (ppm) relative to tetramethylsilane (TMS) as an internal standard,     determined at 300 MHz using perdeuterio DMSO (CD₃SOCD₃) as the     solvent unless otherwise stated; coupling constants (J) are given in     Hz; -   (vii) chemical symbols have their usual meanings; SI units and     symbols are used; -   (viii) solvent ratios are given in percentage by volume; -   (ix) mass spectra (MS) were run with an electron energy of 70     electron volts in the chemical ionisation (APCI) mode using a direct     exposure probe; where indicated ionisation was effected by     electrospray (ES); where values for m/z are given, generally only     ions which indicate the parent mass are reported, and unless     otherwise stated the mass ion quoted is the positive mass     ion−(M+H)⁺; -   (x) LCMS characterisation was performed using a pair of Gilson 306     pumps with Gilson 233 XL sampler and Waters ZMD4000 mass     spectrometer. The LC comprised water symmetry 4.6×50 column C18 with     5 micron particle size. The eluents were: A, water with 0.05% formic     acid and B, acetonitrile with 0.05% formic acid. The eluent gradient     went from 95% A to 95% B in 6 minutes. Where indicated ionisation     was effected by electrospray (ES); where values for m/z are given,     generally only ions which indicate the parent mass are reported, and     unless otherwise stated the mass ion quoted is the positive mass     ion−(M+H)⁺ and -   (xi) the following abbreviations are used:

DMF N,N-dimethylformamide; THF tetrahydrofuran; DCM dichloromethane; HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; Boc tert-butoxycarbonyl; and MeOH methanol.

EXAMPLE 1

This Example illustrates the preparation of N-[1-(N-phenyl-N-cyclobutanecarbonyl-2-ethylamino)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide (Compound No. 1 of Table I).

To a solution of cyclobutane carboxylic acid (50 mg, 0.5 mmol) in dichloromethane (DCM) (10 mL) was added oxalyl chloride (64 mg, 0.5 mmol) and the resulting mixture was stirred at room temperature for 5 h. The mixture was evaporated and the residue was dissolved in DCM (10 mL). N-[1-(N-Phenyl-2-ethylamino)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide (150 mg, 0.43 mmol) was added followed by N,N-diisopropylethylamine (1.5 mmol). The resulting mixture was stirred at room temperature for 20 h, then partitioned between water and ethyl acetate. The organic phase was dried and evaporated. The crude product was purified by eluting through a 20 g Bond Elut cartridge with a gradient of 0-30% methanol in ethyl acetate yielding the title compound (67 mg); ¹H NMR: δ 1.23 (br d, 1H), 1.36 (br d, 1H), 1.6 (m, 4H), 1.92 (m, 2H), 2.05 (m, 3H), 2.30 (m, 2H), 2.61 (s, 1H), 2.80 (s, 3H), 2.9-3.8 (m, 7H), 4.20 (m, 1H), 7.05 (m, 3H), 7.20 (d, 3H), 7.38 (m, 3H); MSS:452.

Compound No. 3 of Table I was prepared in a similar manner:

-   -   ¹H NMR: δ0.61 (m, 2H), 0.76 (m, 2H), 1.30 (br dd, 2H), 1.50 (m,         2H), 1.90 (br q, 2H), 2.30 (br s, 2H), 2.60 (s, 1H), 2.80 (s,         3H), 3.2-3.8 (m, 6H), 4.18 (m 1H), 7.05 (m 3H), 7.20 (m 2H),         7.32 (d, 2H), 7.40 (m, 2H).

Methods

Starting materials are commercially available, have been described in the literature or can be prepared by adaptation of literature methods. Examples of literature methods include: P. Richter, Ch. Garbe and G. Wagner, E. Ger. Pharmazie, 1974, 29(4), 256-262; C. Oniscu, D. Nicoara and G. Funieru, “4-(Ureidosulfonyl)phenylacetic acid and its ureide”, R079-966646, (Romanian document); and M. A. Zahran, M. M. Ali, Y. A. Mohammed and A. A. Shehata, Int. J. Chem., 1993, 4(3), 61.

To a solution of 1-(N-phenyl-2-ethylamino)-4-methylaminopiperidine (466 mg, 2.0 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added 4-fluorophenylacetic acid (323 mg, 2.1 mmol), HATU (800 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.4 mL) and the resulting mixture was stirred at room temperature for 20 h. Water was added and the resulting mixture extracted with ethyl acetate. The organic extract was dried and evaporated affording the title compound (340 mg); ¹H NMR: 1.40 (m, 2H), 1.70 (m, 2H), 2.65 (m, 2H), 2.80 (s, 3H), 2.9-3.2 (m, 5H), 3.70 (m, 3H), 4.23 (m 1H), 6.55 (m, 3H), 7.02 (m, 4H), 7.20 (m, 2H); MS: 370.

To a solution of 1-(2-anilinoacetyl)-4-Boc-aminopiperidine (3.33 g, 10.0 mmol) in THF (100 mL) was added lithium aluminium hydride (20 mL 1M in THF) and the resulting mixture stirred at reflux for 16 h. After cooling to room temperature the reaction was treated with 2M aqueous sodium hydroxide solution and the resulting mixture was filtered. The filtrate was evaporated then redissolved in ethyl acetate. This solution was washed with water, dried and evaporated giving the title compound as an oil (2.1 g); ¹H NMR: 1.21 (dq, 2H), 1.75 (br d, 2H), 1.97 (dt, 2H0, 2.26 (m, 4H), 2.45 (t, 2H), 2.81 (br d, 2H), 3.07 (q, 2H), 5.27 (t, 1H), 6.49 (t, 1H), 6.55 (d, 2H), 7.04 (t, 2H); MS: 234.

To a solution of 4-Boc-aminopiperidine (7.0 g, 35 mmol) in (DMF) (100 mL) was added 2-anilinoacetic acid (4.89 g, 33 mmol), HATU (13.3 g, 35 mmol) and N,N-diisopropylethylamine (6.1 mL) and the resulting mixture was stirred at room temperature for 20 h. Water was added and the resulting precipitate collected and dried affording the title compound as a solid (8.2 g, 74%); ¹H NMR: 1.39 (s, 9H), 1.76 (br t, 2H), 2.75 (m, 1H), 3.04 (m, 1H), 3.5 (m, 3H), 3.84 (m, 3H), 4.20 (br d, 1H), 5.42 (t, 1H), 6.55 (t, 1H), 6.60 (d, 2H), 6.85 (m, 1H), 7.05 (t, 2H); MS: 278 (MH⁺-2-butene).

To a mixture of N-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (2.0 g, 6.2 mmol) and N-(2-chloroethyl)aniline hydrochloride (1.2 g, 6.2 mmol) (J. Med. Chem. 1965, 173) in 4-methyl-2-pentanone (15 mL) was added potassium carbonate (2.56 g, 18.6 mmol) and potassium iodide (150 mg, 0.9 mmol) and the resulting mixture stirred at reflux for 20 h. After cooling to room temperature the solid was removed by filtration and the filtrate concentrated. The residue was purified by Bond Elut chromatography (eluent 5% MeOH/DCM) to afford, after trituration with diethyl ether, the title compound as a white solid (1.30 g, 50%); ¹H NMR (d6 DMSO, 373K): 1.1 (t, 3H), 1.4 (m, 2H), 1.8 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 3.1 (m, 5H), 3.3 (q, 2H), 3.8 (s, 2H), 5.0 (m, 1H), 6.6 (m, 3H), 7.1 (dd, 2H), 7.5 (d, 2H), 7.8 (d, 2H); MS: 444.

To a solution of N-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenyl-acetamide (34 g, 82 mmol) in ethanol (600 ml) was added ammonium formate (40 g). The mixture was purged with argon and 30% Pd on carbon (4.2 g) was added. The resulting mixture was stirred at reflux for 4 h, then allowed to cool and filtered through diatomaceous earth. The filtrate was evaporated to give a thick oil which solidified on standing to yield the title compound (24.9 g. 77 mmol); ¹H NMR: 1.02 and 1.15 (t, 3H), 1.4 -1.6 (br m, 4H), 2.45 (m, 2H), 2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.32 (q, 2H), 3.72 and 4.18 (m, 1H), 3.80 and 3.87 (s, 2H), 7.50 (m, 2H), 7.85 (m, 2H); MS: 325.

To a solution of 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride (32.0 g, 110 mmol) in DCM (500 mL) was added N,N-diisopropylethylamine (60 mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25.0 g, 117 mmol), 4-dimethylaminopyridine (2.0 g) and dicyclohexylcarbodiimide (25.0 g, 121 mmol) were added and the resulting mixture was stirred at room temperature for 20 h. The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous HCl, water and 1N aqueous NaOH, dried (MgSO₄) and evaporated. The residue was purified by silica gel chromatography (eluent 10% MeOH/ethyl acetate) to afford the title compound (35 g, 76%); ¹H NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70 and 4.10 (m, 1H), 7.2-7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415.

To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mmol) and methanol (50 mL) and the resulting mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was added portionwise and the resulting mixture stirred at room temperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K₂CO₃) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the title compound as a solid (38 g); ¹H NMR (CDCl₃): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219.

This was prepared by reacting N-4-piperidinyl-N-ethyl-4-fluorophenylacetamide with N-(2-chloroethyl)aniline hydrochloride according to the procedure used for Method 4; ¹H NMR: 1.0 and 1.5 (t, 3H), 1.3 (m, 1H) 1.5 (m, 1H), 1.7 (m, 2H), 2.0 (m, 2H), 2.4 (m, 2H), 2.9 (m, 2H), 3.1 (m, 2H), 3.2 (m, 2H), 3.6 and 3.7 (s, 2H), 4.1 (m, 1H), 5.2 (br s, 1H), 6.5 (m, 3H), 7.0 (dd, 2H), 7.1 (dd, 2H), 7.2 (m, 2H); MS: 384.

This was prepared by reacting N-(1-phenylmethyl-4-piperidinyl-N-ethyl-4-fluoro-phenylacetamide according to the procedure used for Method 5; ¹H NMR: (formic acid salt): 0.97 and 1.10 (t, 3H), 1.46 and 1.62 (m, 2H), 1.8-2.0 (m, 2H), 2.78 (m, 2H), 3.1-3.3 (m, 4H), 3.65 and 3.74 (s, 2H), 3.97 and 4.22 (m, 1H), 7.08 (m, 2H), 7.25 (m, 2H), 8.42 (s, 1H); MS: 265.

This was prepared by reacting 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride with 4-fluorophenylacetic acid according to the procedure used for Method 6; ¹H NMR (CDCl₃): 1.13 and 1.19 (t, 3H), 1.35 and 1.85 (m, 2H), 1.74 and 2.08 (m, 2H), 2.90 (br m, 2H), 3.30 (m, 2H), 3.46 (s, 2H), 3.66 (s, 2H), 3.55 and 4.42 (m, 1H), 7.00 (m, 2H), 7.2-7.3 (m, 7H); MS: 355.

EXAMPLE 2

The ability of compounds to inhibit the binding of RANTES or MIP-1α was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with 0.1 nM iodinated RANTES or MIP-1α, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES or MIP-1α bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated RANTES or MIP-1α was calculated (IC₅₀). Certain compounds of formula (I) had an IC₅₀ of less than 50 μM. 

1. A compound of formula (I):

wherein: R¹ is C₃₋₇ cycloalkyl; R² is phenyl, heteroaryl, phenyl(C₁₋₄ alkyl) or heteroaryl(C₁₋₄ alkyl); R³, R^(3a), R⁴ and R^(4a) are, independently, hydrogen or C₁₋₄ alkyl; R⁵ is hydrogen, C₁₋₄ alkyl (optionally substituted by halogen, hydroxy, C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, SH, C₁₋₄ alkylthio, cyano or S(O)_(q)(C₁₋₄ alkyl)), C₃₋₄ alkenyl, C₃₋₄ alkynyl or C₃₋₇ cycloalkyl; R⁶ is phenyl, heteroaryl, phenylNH, heteroarylNH, phenyl(C₁₋₂)alkyl, heteroaryl(C₁₋₂)alkyl, phenyl(C₁₋₂ alkyl)NH or heteroaryl(C₁₋₂ alkyl)NH; wherein the phenyl and heteroaryl rings of any of the foregoing are independently optionally substituted by halo, cyano, nitro, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, S(O)_(m)C₁₋₄ alkyl, S(O)₂NR¹¹R¹², NHS(O)₂(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, NHC(O)NH₂, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃, CHF₂, CH₂F, CH₂CF₃ or OCF₃; R¹¹ and R¹² are, independently, hydrogen or C₁₋₄ alkyl; m, and q are, independently, 0, 1 or 2; or a pharmaceutically acceptable salt thereof or a solvate thereof.
 2. A compound of fonnula (I) as claimed in claim 1 wherein R² is phenyl optionally substituted by halogen or CF₃.
 3. A compound of formula (I) as claimed in claim 1 wherein R³ and R^(3a) are both hydrogen.
 4. A compound of formula (I) as claimed in claim 1 wherein R⁴ is hydrogen or methyl and R^(4a) is hydrogen.
 5. A compound of formula (I) as claimed in claim 1 wherein R⁵ is hydrogen, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkyl(C₁₋₄ alkyl).
 6. A compound of formula (I) as claimed in claim 1 wherein R⁶ is benzyl singly substituted by S(O)₂(C₁₋₄)alkyl or S(O)₂NR⁹R¹⁰; wherein R⁹ and R¹⁰ are, independently, hydrogen or C₁₋₄ alkyl.
 7. A process for the preparation of a compound of formula (I) as claimed in claim 1, the process comprising reacting a compound of formula (II):

with either an acid halide of formula R¹C(O)Cl in a suitable solvent, or an acid of formula R¹CO₂H in the presence of a suitable coupling agent and in a suitable solvent.
 8. A phannaceutical composition which comprises a compound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
 9. A compound of formula (I) as claimed in claim 1, wherein R¹ is C₃₋₇ cycloalkyl, R² is phenyl optionally substituted by halogen or CF₃, R³ and R^(3a) are both hydrogen, R⁴ is hydrogen or methyl and R^(4a) is hydrogen, R⁵ is hydrogen, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkyl(C₁₋₄ alkyl), R⁶ is benzyl singly substituted by S(O)₂(C₁₋₄)alkyl or S(O)₂NR⁹R¹⁰; wherein R⁹ and R¹⁰ are, independently, hydrogen or C₁₋₄ alkyl.
 10. A pharmaceutical composition as claimed in claim 8, wherein R¹ is C₃₋₇ cycloalkyl, R² is phenyl optionally substituted by halogen or CF₃, R³ and R^(3a) are both hydrogen, R⁴ is hydrogen or methyl and R^(4a) is hydrogen, R⁵ is hydrogen, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkyl(C₁₋₄ alkyl), R⁶ is benzyl singly substituted by S(O)₂(C₁₋₄)alkyl or S(O)₂NR⁹R¹⁰; wherein R⁹ and R¹⁰ are, independently, hydrogen or C₁₋₄ alkyl. 